Reducing glucocorticoid burden in lupus with omega-3 fatty acids: docosahexaenoic acid augments prednisone efficacy in maintaining cyclophosphamide-induced remission of preclinical lupus nephritis

Abstract Background Managing lupus nephritis (LN) remains challenging due to relapses after immunosuppressive induction and toxicity from long-term glucocorticoid (GC) maintenance therapy. Dietary omega-3 fatty acids prevent LN onset in preclinical models, but their role in maintaining remission post-induction remains unstudied. Methods The silica-accelerated LN (SALN) model using lupus-prone NZBWF1 mice was used to evaluate how docosahexaenoic acid (DHA), an omega-3 fatty acid, influenced LN remission durability after cyclophosphamide (CYC) induction, alone or with a moderate dose of prednisone (PDN). Mice received intranasal silica weekly from 8 to 11 weeks. After LN developed at 21 weeks, groups were injected weekly with CYC (human equivalent dose [HED]=31 mg/day) or vehicle (VEH) for 8 weeks, during which CYC groups also received control, DHA (HED=5 g/day), PDN (HED=9 mg/day), or DHA+PDN diets. Disease activity was monitored via proteinuria, autoantibodies, and survival. Six weeks post-CYC, multi-organ histopathology and immunohistochemistry were assessed. Results VEH-treated mice developed severe LN with early death. CYC slowed disease temporarily in control- and PDN-fed mice; relapses occurred after cessation. DHA or DHA+PDN increased tissue omega-3 levels and prolonged remission. PDN and DHA monotherapies and co-therapy improved survival, but DHA+PDN was most effective at sustaining remission as reflected by reduced histopathologic markers of lupus severity in the kidney, spleen, lung, and brain. Conclusion DHA+PDN optimally maintained LN remission after CYC, supporting omega-3 supplementation as a potential GC-sparing strategy to improve immunosuppressive therapy and prevent relapses. Highlights Frequent post-immunosuppressive treatment flares and the toxicity from long-term maintenance therapy with glucocorticoids (GCs) limit effective management of lupus nephritis (LN). The silica-accelerated lupus nephritis (SALN) model in NZBWF1 mice mimics the gene–environment interactions of human systemic lupus erythematosus (SLE) and LN, enabling synchronized and efficient preclinical studies of drug and nutritional interventions. Short-term immunosuppressive therapy with cyclophosphamide (CYC) induces temporary remission of LN and extrarenal inflammation and autoimmunity in SALN mice, which can be extended through monotherapy with either dietary supplementation with omega-3 docosahexaenoic acid (DHA) or a moderate dose of the GC prednisone (PDN). Combined maintenance therapy with DHA and PDN proved more effective than monotherapy in enhancing the durability of post-CYC LN remission and in reducing extrarenal inflammation and autoimmunity in the lung, spleen, and brain. These preclinical findings show that dietary supplementation with omega-3s such as DHA may offer a safe, affordable, GC-sparing adjunctive option for managing LN and SLE.